|Numéro de publication||US5830173 A|
|Type de publication||Octroi|
|Numéro de demande||US 08/904,821|
|Date de publication||3 nov. 1998|
|Date de dépôt||1 août 1997|
|Date de priorité||12 déc. 1994|
|État de paiement des frais||Payé|
|Autre référence de publication||US5725493, US6251090|
|Numéro de publication||08904821, 904821, US 5830173 A, US 5830173A, US-A-5830173, US5830173 A, US5830173A|
|Inventeurs||Robert Logan Avery, Jeffrey Kevin Luttrull|
|Cessionnaire d'origine||Avery; Robert Logan, Luttrull; Jeffrey Kevin|
|Exporter la citation||BiBTeX, EndNote, RefMan|
|Citations de brevets (11), Citations hors brevets (18), Référencé par (148), Classifications (6), Événements juridiques (16)|
|Liens externes: USPTO, Cession USPTO, Espacenet|
This application is a division of our parent application Ser. No. 08/353,804, filed Dec. 12, 1994, for INTRAVITREAL MEDICINE DELIVERY, now U.S. Pat. No. 5,725,493, but copending with the present application.
This invention pertains to intravitreal medicine delivery and more particularly to an implant device for delivering medicine to the vitreal cavity of the eye, and to a method for introducing medicines into the vitreal cavity using the device.
Within the past several decades, great advances have been made in the diagnosis and treatment of vitreoretinal diseases. Advances in laser technology, and vitreoretinal surgical techniques, have significantly improved the prognosis of numerous retinal conditions including diabetic retinopathy, macular degeneration, and retinal detachment. As the pathophysiology of these and many other vitreoretinal diseases is also becoming more clearly understood, a host of potential pharmacological agents is currently under investigation.
In addition to the numerous antibiotic, antiviral, and antifungal agents currently used to treat infections of the retina and vitreous, many antiinflammatory and anticancer drugs have been shown to be useful in treating diseases such as proliferative vitreoretinopathy. As the role of growth factors involved in diabetic retinopathy, macular degeneration, and other retinal degenerations is elucidated, new classes of agents have been found to be of possible benefit, including growth factors themselves, blocking antibodies to growth factors, antisense oligonucleotides, and even gene therapy with growth factor inserts.
Unfortunately, the delivery of drugs to the retina is often problematic. Most agents given topically to the eye (in the form of eye drops) do not penetrate through the anterior segment of the eye well enough to reach the vitreous or retina in therapeutic concentrations. Medications can be given orally or intravenously, but the blood vessels within the retina (and other parts of the central nervous system) are relatively impermeable to many agents. Furthermore, these drugs may have significant systemic side effects on other organs of the body. Drugs can be directly injected into the vitreous cavity, via a needle passed through the pars plana, and this technique is currently employed to combat certain severe, sight-threatening infections. However, this procedure itself en tails certain risks, such as infection, bleeding, cataract formation, and retinal detachment. Furthermore, the majority of the injected drug is often cleared from the vitreous cavity within several days, necessitating multiple injections for prolonged treatment.
Accordingly, devices have been developed for improving the introduction of drugs to the vitreal cavity. One such device is a biodegradable polymer designed to be injected into the vitreous cavity where it slowly releases drug as it dissolves. A similar drug-containing polymer has been developed which is made in the shape of a tack or plug to be surgically inserted into the eyewall at the pars plana so that it projects into the vitreous cavity. Liposomes containing pharmacological agents have been developed to slowly release the agent after injection into the vitreous cavity. Another device is a plastic pellet which contains a retinal drug (ganoclovir) and is sutured inside of the vitreous cavity where the drug slowly dissolves into the cavity.
Although such devices as those briefly referred to above are apparently effective in delivering drugs into the vitreous cavity, they have significant disadvantages. First, all of these devices contain a certain amount of drug which when expended cannot be replenished without repeating the surgical implantation or intravitreal injection. Although these different devices can release drugs for weeks to months (or in the case of the plastic pellet, almost one year), certain indications for intravitreal drug administration require extended or lifetime therapy. Therefore, multiple procedures are often required and are highly undesirable.
Secondly, the device with the longest release rate, the plastic pellet of ganiclovir, requires a very large eyewall incision (5 mm) to implant due to its large size. Although the other devices can be implanted or injected through a smaller incision (1 mm or less), those that are injected freely into the vitreous cavity instead of anchored to the eyewall can migrate within the eye and come in direct contact with the retina where they can block vision or release high local concentrations of drug which could potentially prove toxic to delicate retinal tissue.
Third, many pharmacological agents cannot easily and effectively be incorporated into biodegradable polymers. Furthermore, many potential pharmacological agents would not remain stable for extended periods of time in the vitreous cavity. Therefore, there is a significant limitation to what pharmacological agents can be administered via the slow release devices currently available.
Fourth, since the plug or pellet is in essence the drug itself, treatment is limited to this drug, so that another surgery or procedure is required to change it if administration of a different drug is desired.
The present invention is directed to intravitreal medicine delivery involving an implant device and method wherein a wide variety of beneficial drugs or other pharmacological agents or medicines can be introduced into the vitreous cavity over an extended period of time, as much as the life of the patient, with only a single initial surgery to implant the device; wherein the surgical incision needed for implantation is minimized; wherein additional amounts of drugs over an initial supply can be introduced without further invasive surgery; wherein the type of medicine can be varied or changed depending on such factors as the disease being treated or drug availability; wherein the dosage of agent being administered is controllable; and wherein damage or interference by the implant to various parts of the eye is avoided.
It is an object of the present invention to provide for improved delivery of drugs and other pharmacological agents to the vitreous cavity of the eye, especially for treating vitreoretinal diseases.
Another object is to enable medicinal agents to be delivered to the vitreous cavity with a single initial surgery and without the need for repeated invasive surgeries or procedures.
Yet another object of this invention is to allow replenishment of the drug or other medicinal agent within an implant attached to the eyewall by injection into the implant through the conjunctivae and not through the eye wall.
A further object is to be able to change the pharmacological agent being dispensed from an eye implant device into the vitreal cavity, without surgery or other invasive procedure.
It is also an object to control the dosage of drugs or other pharmacological agents delivered to the vitreous cavity from an implant device.
Still another object of the present invention is to enable the patient to control delivery of dosages of medicines to the vitreous cavity with a delivery device implanted on the patient's eyeball.
It is a still further object to implant an intravitreal medicine delivery device which dispenses medicine into the vitreous cavity without interference with or damage to various parts of the eye.
Yet another object of the present invention to prevent inadvertent puncture of the eyeball by an injection needle used to replenish the Supply of drugs or other agents in an eye implant device.
It is also an object of the subject invention to prevent an uncontrolled movement of medicines into the vitreous cavity from an intravitreal delivery implant when the supply of medicines in the implant is being replenished in situ.
Another object of this invention is to filter medicines being dispensed from an implant device before being admitted to the vitreous cavity thereby to prevent unwanted particulate matter, such as undissolved biodegradable polymer, from moving into the cavity, while allowing medicines to pass into the cavity.
It is a feature of the present invention to have a relatively large drug or other medicine-containing reservoir which is located outside the eyewall in the sub-conjunctival space and which is connected to the vitreous cavity by a smaller tube through the pars plana so that a substantial amount of medicine can be brought into the vitreous cavity with a minimum of eyewall incision.
It is another feature of this invention to provide an intravitreal medicine delivery device with a pump for moving predetermined doses of drugs or other agents into the vitreous cavity and which can be operated by the patient.
It is another feature to provide an intravitreal drug delivery device which has a low profile for closely-fitting implantation under the conjunctiva and Tenon's capsule of the eyeball.
It is another feature of this invention to provide an eye implant device with an injection port which can be readily identified through overlying tissue for injecting an additional supply of medicine into the implant device.
Still another feature of this invention is to suture a medication delivery implant device to the eyewall so that it facilitates subsequent injections of medication into it while maintaining its implanted position.
These and other objects, features, and advantages of the subject invention will become apparent upon reference to the accompanying drawings, the following description, and the appended claims.
FIG. 1 is a plan view of one embodiment of an intravitreal medicine delivery device according to the present invention shown implanted on a human eyeball, which is schematically shown, it being understood that both the device and the eyeball are enlarged from actual size.
FIG. 2 is a cross-section taken along line 2--2 of FIG. 1.
FIG. 3 is an isometric view of the subject intravitreal medicine delivery device, even further enlarged from the size in FIG. 1 and showing the three principle parts of the device, namely, a housing, a tube, and an elbow.
FIG. 4 is a plan view of the intravitreal medicine delivery device shown in FIG. 3.
FIG. 5 is a side elevation of the device shown in FIG. 4.
FIG. 6 is a cross-section along line 6--6 of FIG. 4.
FIG. 7 is a cross-section along line 7--7 of FIG. 4.
FIG. 8 is a greatly enlarged schematic view of an eye showing the subject intravitreal medicine delivery device implanted on the eyeball and representing the eyelid being lifted to expose the region of the eye where the implant is located.
FIG. 9 is similar to FIG. 8, still enlarged but on a smaller scale, and demonstrating how the injection port of the subject device can be readily identified through overlying tissue.
FIGS. 10 and 11 are both cutaway, sectional views of a portion of the intravitreal medicine delivery device of the present invention illustrating a valve in the elbow, with FIG. 11 showing the valve in a different position from FIG. 10.
FIGS. 12a-12e are schematic views showing the sequence of positions of the valve of FIGS. 10 and 11.
FIG. 13 is a cutaway sectional view of a portion of the subject delivery device and showing an optional feature in the tube of the device.
FIG. 14 is a plan view of a portion of the subject medicine delivery device, but depicting another embodiment of the housing of the device.
FIG. 15 is a side elevation of the embodiment of FIG. 14.
FIG. 16 is a cross-section along line 16--16 of FIG. 14.
FIG. 17 is a plan view of a portion of the subject delivery device but depicting still another embodiment of the housing.
FIG. 18 is an isometric view of another embodiment of an elbow of the subject delivery device which differs from the elbow shown in FIG. 3.
FIG. 19 is also an isometric view of still another embodiment of the elbow.
The first embodiment of an intravitreal medicine delivery device of the resent invention is identified in FIGS. 1-6 by the numeral 30 and is shown in FIGS. 1 and 2 as being implanted on a human eyeball or globe 34. The eyeball is shown schematically and in just enough detail to enable an understanding of the present invention. Certain parts of the eye are thus briefly identified with reference numerals. Schematically represented in either or both of FIGS. 1, 2, 8 and 9 are the cornea 36, the sclera 38, the conjunctiva and Tenon's capsule 44, the iris 46, the retina 50, the lens 56, the eyelid 60, eyelashes 62, the vitreous cavity 66, the pars plana 68, the superior rectus muscle 72, and the lateral rectus muscle 74.
The first embodiment of the intravitreal delivery device 30 is shown in detail in FIGS. 3-7 and is now described. The device includes a housing 80 most of which is preferably pre-formed of semi-rigid material to have a concavo-convex shape and a low profile so as during surgery to fit easily and closely against an eyeball, as 34. In plan view the housing preferably has a generally rectangular outline (FIG. 4) or a trapezoidal outline (FIG. 17) but is this outline may be varied to facilitate implantation as will be understood by those skilled in the art.
The housing 80 (FIGS. 3-6) has a base or bottom wall 84 which has an outwardly, spherically concave shape or curvature generally complementary to the curvature of the eyeball 34. This bottom wall is made of a tough material impenetrable by an injection needle or syringe and is preferably of a plastic, such as nylon, Kevlar, or polymethyl methacrylate (PMMA), but may be made of metal, such as tantalum. The housing also has a top or upper wall 86 which has an outwardly spherically convex shape and is joined in a fluid-tight manner to the bottom wall along a peripheral edge 90. The top and bottom walls may be one-piece and integral along the edge or of two different pieces sealed along the edge. This edge has an anterior segment 92, a posterior segment 94, and lateral segments 96 and 97 which meet at four corners of the housing. Outer corner fixation tabs 98 project from the anterior corners of the housing and have suture-receiving eyelets 100. Spaced, inner anterior fixation tabs 102 project from the anterior segment 92 and also have suture-receiving eyelets 104.
The spaced top and bottom walls 86 and 84 (FIGS. 5 and 6) provide a fluid-tight storage reservoir or chamber 110 in the housing 80. This reservoir has a maximum height dimension indicated by the numeral 112 and measured radially of the curved top and bottom walls and where the spacing between the walls is the greatest. As an example but not limiting to the invention, this maximum height dimension is preferably about 3-4 mm. Of course, the height of the reservoir tapers downward toward all four segments 92, 94, 96 and 97 (FIGS. 3, 5 and 6) of the edge 90. It is also noted that the lateral dimensions of the reservoir, that is the length and width dimensions, measured generally spherically of the walls, are relatively much greater than the maximum height. For the embodiment shown in FIG. 4, but again not limiting to the invention, the width or distance between lateral edges 96 and 97 is approximately 1.5 cm and the length or distance between the anterior and posterior edges 92 and 94 is approximately 1 cm.
Of particular significance, however, is that the top wall 86 (FIGS. 3-6) of the housing 80 has a slightly uplifted, arcuate, anterior medicine-injection port or area 122 closely adjacent to the anterior edge 92 and having opposite ends 123 closely adjacent to the anterior corners of the housing. The top wall also has a main or remainder portion 124 of greater area than the injection port. This main portion is of the same material as the bottom wall 84 and is the part of the top wall which is joined to the bottom wall. Thus, this main portion is needle-impenetrable and fluid-impervious.
The injection port 122 (FIGS. 3-6), however, is of a material, such as silicone rubber, which is penetrable by a needle or syringe but which reseals itself when the needle is withdrawn so that the port is normally fluid-impervious. An important feature of the port is that the material thereof is colored, for example, blue, as indicated in the drawings. This coloration is important to provide a marker or identification mark which is visible exteriorly of the eye, especially through covering tissue or patches, to facilitate location of the port by attending medical personnel.
The reservoir 110 (FIGS. 5 and 6) has an anterior fluid outlet 130 located in the top wall 86 of the housing 80 between the anterior edge 92 and the injection port 122 and is thus between the inner tabs 102. A filter 134 is optionally mounted in the outlet to prevent particulate materials, such as biodegradable polymer, from passing out of the reservoir and into the vitreous cavity, while permitting medicines released from the dissolving polymers to pass out of the reservoir 110 and into the cavity. This filter may take various forms such as a semi-permeable, osmotic membrane or a porous cellulose filter such as a Millipore filter. Furthermore, it may be a thin capillary tube, or coil of capillary tube, designed to restrict the flow of drug-containing fluid from the reservoir 110 into the vitreous cavity 66.
The subject intravitreal medicine delivery device 30 also includes a tapered, elongated delivery tube 140 (FIGS. 3-7) of fluid-impervious compressible elastomeric material, such as a silicone elastomer, thus providing a fluid passageway or lumen 144. Preferably, the tube is of oval cross-section as illustrated, but is not limited to this cross-section. The tube has a low or flat profile, like the housing, and includes a base and upper walls 146 and 148 which are joined at lateral edges. The passageway has a relatively small minor axis or dimension, as best seen in FIG. 7, which is preferably less than the height maximum height dimension 112 of the reservoir 110. Again, although not limiting to the invention, this minor axis is preferably about the size of a 19-20 gauge lumen. The base wall may be outwardly convex, as shown, or concave to conform to the curvature of the eyeball. Significantly, the top wall is resiliently compressible toward the base wall by applying slight digital pressure against the wall to constrict the passageway. When the pressure is relieved, the top wall returns to its normally relaxed position with the passageway fully open.
The tube 140 (FIGS. 3-7) has a relatively wide proximate end 150 connected to the housing 80 around the outlet 130 so that the passageway 144 is in fluid communication with the reservoir 110. In effect, the passageway is an extension of the reservoir so that the reservoir and the passageway together constitute one large storage reservoir or chamber. The tube converges anteriorly from the housing to a relatively narrow distal end 152, it being noted that the major axis of the passageway thus varies from a maximum at the proximate end to a minimum at the distal end. As shown in FIGS. 5 and 6, the tube is preferably preformed with, and has sufficient rigidity to maintain, a longitudinal curvature complementary to the curvature of an eyeball, but is sufficiently flexible to allow limited flexing at the juncture of the tube and the housing.
The subject delivery device 30 (FIGS. 3-6) also includes a semi-rigid tubular elbow 160 having an in-line connector sleeve 162 attached to the distal end 152 of the tube 140 and an intravitreal extension 164 which projects from the sleeve at an angle to the in-line sleeve, preferably of about eighty to ninety degrees, and terminates in a tip 166. The sleeve is of about the same diameter as the minor axis or height of the tube, as best seen in FIG. 7, and although given by way of example only, is about 19-20 gauge. The elbow thus provides a lumen or fluid passageway 168 in fluid communication with the passageway in the tube and opening at the tip. Another pair of fixation tabs 172 project laterally from the sleeve 162 of the elbow 160 and have suture eyelets 174. The elbow may be made of the same material as the housing.
Once again, to provide an example of a preferred embodiment of the intravitreal delivery device 30 (FIG. 4) but not limiting to the invention, the length of the combined tube 140 and elbow 160, from the anterior segment 92 to the bend of the elbow, is about 7 mm, and the maximum transverse dimension of the tube at its proximate end is about 3 mm.
The method of the present invention and use of the subject delivery device 30 are best described by reference to FIGS. 1, 2, 8 and 9. The delivery device is implanted within the socket of the eye on the episcleral surface of the globe (eye wall) 66 by placing the device under the conjunctiva 44 and Tenon's capsule. The device is located between the superior and lateral rectus muscles 72 and 74 with the base wall 84 fitted against the eyeball 34 and the anterior edge 92 located posteriorly of the muscle roots and slightly posteriorly of the equator of the eyeball, as best seen in FIG. 1. Thusly located, the injection port 122 faces anteriorly, and the tube 140 projects anteriorly with the tip 166 at the pars plana 68.
A hole 188 (FIG. 2) of about 1.0 mm is incised through the eyeball 34 at the pars plana 68 and into the vitreous cavity 66. The intravitreal extension 164 of the elbow 160 is inserted through the hole so that it projects into the cavity a distance of preferably approximately 4 mm. In this regard, it is to be noted that the rigidity of the elbow allows the position of the intravitreal extension 164 to be controlled as it is inserted into the cavity so as to avoid contact of the tube with the lens 56, cornea 36 or iris 46. The device 30 is then attached to the episclera 38 with sutures 184 (FIG. 1) in selected eyelets 100 (and/or 104) and eyelets 174 (FIG.4). The tabs 98 and 102 are provided as alternates in case one location or the other is preferred for the sutures. After suturing the device in place, a sceral patch or graft 190 (FIG. 8) is sutured over the tube 140 for the purpose of preventing of erosion of the implant tube through the conjunctiva, which could lead to infection and require removal of the implant. The rigidity of the elbow and its attachment to the sclera (FIGS. 1 and 2) maintain the intravitreal extension of the implant tube in the position in which it is initially placed so that it does not move around in the cavity as the implant is worn and used by the patient.
A supply of medicine 194 (FIG. 2) is placed in the reservoir 1 10 before or after implantation. Examples of drugs that may be used are antivirals, antibiotics, steroids, growth factors or inhibitors, anti-sense oligonucleotides, mediators of gene therapy, and others. These may be in the form of fluids, solids, suspensions, emulsions, slow-release or time-release beads, capsules, liposomes, ion-exchange beads, biodegradable polymers, pellets, or other micro-particulate vehicles. As an example, the medicine 194 is shown as time-release beads in FIG. 2.
If drugs or other agents are injected after the implant surgery, the eyelid 60 remains lifted (FIG. 8) to expose the region where the device 30 is implanted. Because of its color, the injection port 122 is visible through the conjunctiva tissue 44 covering the device. The tube 140 may be depressed to block the passageway 144 (FIG. 6), and an injection needle 202 of a syringe 200 (FIG. 9) filled with the medicine 194 penetrates the port, and the medicine is injected.
If a large volume of medicine 194 is to be instilled into the reservoir 110 (FIG. 9), either initially or to refill the implant 30 at a later date, venting of the implant reservoir by a second needle, not shown but placed through the injection port 122 simultaneously with injection, may be required. Injection of small volumes of medicine into the reservoir, however, may not require venting.
After the injection is completed (FIG. 9), the needle 202 is withdrawn and the tube 140 is released to expand to normal size (FIG. 2). By blocking the passageway during filling of the reservoir, fluid flow or fluid pressure through the tube and elbow 160 and into the vitreous cavity 66 is precluded. When the needle is withdrawn, the port 122 reseals itself.
Following the implant surgery and as the patient wears the implanted device 30 (FIG. 2), the medicine 194 is thus exposed to the vitreous cavity 66 over an extended period of time. Whether the medicine is in the form of solid material from which the medicine diffuses or whether the medicine is fluid-borne, this exposure through the passageways 144 and 168, allows the medicine to diff-use, flow or otherwise move or pass from the reservoir 110 into the vitreal cavity.
The impetus for diffusion of the medicine 194 from the reservoir 110 into the vitreous cavity 66 occurs for several reasons. First, the concentration gradient between the medicine in the reservoir and vitreous fluid will set up its own diffusion gradient causing a movement of medicine into the cavity. Secondly, the patient can cause frank fluid flow by digitally pressing against the eyelid 60 and thereby against the top wall 148 of the tube 140 to force fluid-borne medicine into the vitreous cavity. Thus, the compressible top wall 148 in combination with the storage reservoir and passageways 144 and 168 may serve as a pump which is generally identified by numeral 210. Thirdly, injection of medicine via reservoir increases pressure in the reservoir driving a net flux of fluid through the tube into the vitreous cavity. Finally, non-al physiologic forces, such as blinking, eye movements, and normal blood pressure pulses, will cause small pressure gradients to develop in the implant tube promoting passage of medicine into the vitreous cavity.
This movement of medicine 194 (FIG. 2) from the storage reservoir 110 into the vitreous cavity 66) will normally continue, or be forced to flow by the patient's pumping of the tube 140, for an extended period of time whereupon it may be necessary to replenish the original supply of the medicine. Also, because of the discovery of a new and better drug or the need for a different drug or other medicine, it may be desirable to change the medication. In any case, the patient returns to the physician's office for the following simple procedure. The eyelid 60 is lifted (FIGS. 8 and 9) and the patient looks down to expose the region of the implanted delivery device 30. The scleral patch 190, the conjunctiva and Tenon's capsule 44 and a fibrous capsule (not specifically shown in the drawings but believed to be well understood), which grows over the device under the conjunctiva obscures the device 30, except for the injection port 122, as illustrated in FIG. 9. The port is visible through the tissue because it is identified with a color which can be seen through the tissue.
While digitally compressing the tube 140 (FIGS. 8 and 9) to block the passageway 144, as previously described, the injection port 122 is penetrated with the syringe needle 202 and a new supply of medicine 194 is injected into the reservoir 110. As previously indicated, venting of the implant reservoir 10 may be required for injection of larger volumes of medicine. Pressure on the tube is released and the needle is withdrawn, the port sealing after the withdrawal. The intravitreal delivery device 30 is then capable of repeating its delivery of medicine to the vitreous cavity 66 over an extended period of time, as previously described. Of prime significance, a repeat surgery to re-introduce a new implant, or another invasive procedure to inject a supply of medicine, is avoided.
A significant relationship between the location of the suturing tabs 98, 102, and 172 and the injection port 122 is to be noted. With reference to FIG. 1, it will be seen that all the sutures 184 are located anteriorly of the port. Thus, when the injection needle 202 (FIG. 9) presses against the port to thrust the needle through the port, the sutured tabs resist posterior movement of the implant device, as 30, and maintain it in its implanted position.
The second embodiment 30a (FIGS. 10-12) of the present invention is the same as the first embodiment except that a valve 250 is incorporated in a the elbow 160 to enhance the pumping action previously described. The valve shown and described is a ball-check valve, but other valves having a similar function can be employed. The valve shown, however, includes a valve body 252 fitted in the connector sleeve 162. The valve body provides an outer chamber 254 having an annular inlet 256 opening into the passageway 144 of the tube 140, an annular outlet 258 opening toward the intravitreal extension 164, an annular valve seat 260 between the inlet and outlet, and a dosage chamber 264 between the valve seat and the outlet. The valve also includes a resiliently expandable, conical mouthpiece 268 of a suitable elastomeric material whose apex is normally closed in its relaxed condition but which opens when fluid pressure inside the valve body, in the direction of the apex, forces it open. Still further, the valve includes a resilient ball 270 in the outer chamber and a spring 272 between the ball and the valve seat.
In operation of the intravitreal delivery device 30a when it incorporates the valve 250 (FIGS. 10-12), the storage reservoir 110 is filled with fluid-borne medicine, as represented by the numeral 280, either during initial manufacture or by subsequent injection through the injection port 122. With reference to the flow diagrams of FIG. 12a-12e, the condition of the valve in its resting state is shown in FIG. 12a wherein the ball 270 floats in the outer chamber 254 being held away from the seat 260 by the spring 272 (FIG. 10). Because of the pressure gradients previously described in regard to the first embodiment, fluid-borne medicine from the reservoir fills not only the passageway 144 but also the outer chamber 254 (FIG. 11) and the dosage chamber 264. Under these conditions, there is insufficient pressure to open the mouthpiece 268.
When a dose of medicine 280 is to be delivered to the vitreous cavity 66, the patient or attendant presses against the patient's eyelid 60 thereby pressing against the tube wall 148 (FIG. 11) compressing the tube 140 and constricting the passageway 144 and exerting a fluid pressure toward the vitreous cavity 66 (FIG. 12b). This pressure increase is sufficient to force the ball 270 against the spring 272 until the ball seals (FIG. 12c) against the seat 260 thereby temporarily blocking fluid flow through the valve. Such pumping action thus causes a limited quantity of fluid, essentially the amount in the dosage chamber 264, that is, the predetermined dose or aliquot, to flow into the vitreous cavity 66. Thus, the valve 250 and the tube 140, working in cooperative relationship with the reservoir 110 and the elbow 160, constitute a pump 210'.
When pressure on the eyelid 60 and thus the tube wall 148 is relieved (FIG. 12d and 12e), a reverse pressure develops because of the lowering of pressure in the passageway 144, whereby the valve ball 270 unseats, and the mouthpiece 268 collapses to its closed position. Fluid pressure in the device then returns to an equilibrium state and the valve returns to its resting state, as shown in FIG. 12e.
The third embodiment 30b of the present invention is the same as the first embodiment 30 except as follows. In FIG. 13, there is illustrated a tube 140' connected to the housing 80 and the elbow 160. A series of tipper and lower baffles 300 and 302 are respectively attached to the top and base walls 148 and 146 of the tube and project into the passageway 144 in interdigitated, spaced relationship. Since the tube is oval, the baffles are semi-oval or semi-elliptical, but if a tube has a different cross-section, the shape of the baffles would be changed to conform. For example, if the tube is circular, the baffles would be semi-circular. The purpose of these baffles is to facilitate closure of the passageway when the walls of the tube are compressed during filling the storage reservoir 110, while allowing flow through the passageway at all other times when the tube is in normally fully expanded or open condition.
The fourth embodiment of the delivery device is identified by the numeral 30c and relates to a different housing construction but is otherwise the same as the first embodiment 30. In FIG. 14, there is shown a housing 80' enclosing a reservoir 110' which is in communication with a tube, such as 140 or 141', which is only partially shown in FIGS. 14-16 since this embodiment does not involve a modification of the tube. The modified housing 80', however, has a base wall 84' like the base wall 84 (FIG. 6) and injection port 122' like the injection port 122 (FIGS. 3-6), but a top wall 86' different from the top wall 86 (FIG. 4). The top wall 86' (FIG. 14) has a main portion 124' including a peripheral section 326 and a medial section or roof 328 located posteriorly of the injection port 122'.
As best shown in FIGS. 14 and 15, the peripheral section 326 (excluding the injection port 122') is made of relatively rigid, impenetrable material, such as described for the base wall 84 and the main portion 124 of the first embodiment 30. The injection port 122' is constructed of the same penetrable, resealable material as the port 122. The medial section 328, however, is made of a softer, flexible and resilient material, such as silicone rubber, to allow the medial section or roof to be compressed and thereafter expand to its relaxed state. In addition, this medial section may be semi-permeable to preclude a vacuum from developing in the reservoir when the tube 140 or 140' is compressed while minimizing any appreciable loss of fluid-borne medicine.
Alternatively, the medial section 328 may be made of an elastomeric material which is distended by the injection of a large volume of medicine into the reservoir 110' via the injection port 122'. The distention of the medial section increases the pressure in the reservoir and forces drug-containing fluid into the tube 140 or 140' where egress into the vitreous is controlled by passage through a filter or capillary tube 134'. Still further, the entire housing 80' may be made of elastomeric material to provide such pressure by distention of the housing.
The fifth embodiment (FIG. 17) involves a differently shaped housing 80", to which reference was previously made. Instead of the housings 80 or 80', each of which has a generally rectangular periphery, the housing of this embodiment has a generally trapezoidal outline in plan view. Such a trapezoidal shape may be preferred to facilitate implantation. The trapezoidal housing has an injection port 122", anterior tabs 98" with suture eyelets 100", and lateral tabs 340 with suture eyelets 342. Again, by way of example only, the preferred dimensions of the trapezoidal housing are similar to the rectangular housing except that the posterior edge is about 1.5 cm and the anterior edge is about 0.75 cm.
An additional feature which may be incorporated in the previously described embodiments of the present invention has two species as shown in FIGS. 18 and 19. In FIG. 18, there is illustrated a tubular elbow 160a having an intravitreal extension 164' in which is provided a plurality of holes or slits 350. A semi-permeable wick, insert, or filter 352 of very flaccid material, such as a silicone sponge, is positioned in the passageway of the extension.
In FIG. 19, a semi-permeable membrane or filter 360 in the shape of a relatively rigidly-formed cup is attached to the open tip 166' of a tubular elbow 160b and projects therefrom.
When either species shown in FIGS. 18 and 19 is incorporated in the intravitreal delivery device 30, 30a or 30c of the present invention, medicine passes from the reservoir 110 through the passageways 144 and 168 and through the wick 352, or the membrane 360, from which it diffuses into the vitreous cavity 66. The wick or membrane is optionally used to obviate the possibility of occlusion of the drug passage into the vitreous cavity by particulate matter from the reservoir.
From the foregoing description of the intravitreal medicine delivery device 30, 30a, 30c and method of the present invention, it will be understood how the device and method result in numerous advantages and provide solutions to various problems experienced by prior art devices and methods. The subject invention enables a wide variety of drugs and other pharmacological agents and medicines to be introduced into the vitreous cavity over the lifetime of the patient with only a single initial surgery and with minimum intraocular invasion to implant the device.
Thereafter, to resupply the device 30 with more medicine or to change the medicine, only a simple injection into reservoir 110 through the specially identifiable injection port 122, 122', or 122" of the device is necessary. No invasive surgery or procedure is needed.
As contrasted with biodegradable polymer pellets directly implanted into the eyeball and which do not lend themselves to many potential pharmacological agents, the subject device 30 is not so limited and can utilize the broad range of medicinal agents now available or becoming available. Moreover, the device 30 and method allow the dosage delivered to the vitreous cavity 66 to be controlled and furthermore, allows the patient to control the timing of the deliveries. Additional features incorporated into the device filter the medicine before it enters the vitreous cavity. Also, the device is designed to facilitate its implantation so that it fits closely and relatively comfortably against the eyeball and so that damage or interference with other parts of the eye are avoided.
Although preferred embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitation.
|Brevet cité||Date de dépôt||Date de publication||Déposant||Titre|
|US3916899 *||7 févr. 1974||4 nov. 1975||Alza Corp||Osmotic dispensing device with maximum and minimum sizes for the passageway|
|US4543088 *||7 nov. 1983||24 sept. 1985||American Hospital Supply Corporation||Self-sealing subcutaneous injection site|
|US4553973 *||1 févr. 1985||19 nov. 1985||Alza Corporation||Process for preparing osmotic device|
|US4751926 *||12 sept. 1986||21 juin 1988||Dow Corning Wright Corporation||Instrument for subcutaneous insertion of an injection reservoir|
|US4760837 *||19 févr. 1987||2 août 1988||Inamed Development Company||Apparatus for verifying the position of needle tip within the injection reservoir of an implantable medical device|
|US4781675 *||27 août 1987||1 nov. 1988||White Thomas C||Infusion cannula|
|US5171213 *||14 août 1991||15 déc. 1992||Price Jr Francis W||Technique for fistulization of the eye and an eye filtration prosthesis useful therefor|
|US5178604 *||31 mai 1990||12 janv. 1993||Iovision, Inc.||Glaucoma implant|
|US5407441 *||31 mars 1993||18 avr. 1995||Greenbaum; Scott||Ophthalmologic cannula|
|US5462739 *||16 nov. 1992||31 oct. 1995||Yeda Research And Development Co., Ltd.||Microdelivery device and method for enhanced drug administration to the eye|
|US5472436 *||26 juil. 1994||5 déc. 1995||Fremstad; Daria A.||Ocular appliance for delivering medication|
|1||*||Eliason et al; An Ocular Perfusion System; Invest. Ophthalmol. Vis. Sci., vol. 19, No. 1, Jan. 1980; pp. 102 105.|
|2||Eliason et al; An Ocular Perfusion System; Invest. Ophthalmol. Vis. Sci., vol. 19, No. 1, Jan. 1980; pp. 102-105.|
|3||*||Hashizoe et al;Scleral Plug of Biodegradable Polymers for Controlled Release in the Vitreous Arch Ophthalmol, vol. 112, Oct. 1994; pp. 1380 1384.|
|4||Hashizoe et al;Scleral Plug of Biodegradable Polymers for Controlled Release in the Vitreous Arch Ophthalmol, vol. 112, Oct. 1994; pp. 1380-1384.|
|5||*||Jabs; Treatment of Cytomegalovirus Retinitis 1992; Arch Ophthlmol, vol. 110, Feb.1992, pp. 185 187. Smith, et al; Intravitreal Sustained Release Ganiclovir; Arch Opthlmol, vol. 110, Feb.1992; pp. 255 258.|
|6||Jabs; Treatment of Cytomegalovirus Retinitis--1992; Arch Ophthlmol, vol. 110, Feb.1992, pp. 185-187. Smith, et al; Intravitreal Sustained-Release Ganiclovir; Arch Opthlmol, vol. 110, Feb.1992; pp. 255-258.|
|7||*||Kimura et al; A New Vitreal Drug Delivery System Using An Implantable Biodegradable Polymeric Device; Investigative Ophthalmology & Visual Science, May, 1994, vol. 35, No. 6; pp. 2815 2819.|
|8||Kimura et al; A New Vitreal Drug Delivery System Using An Implantable Biodegradable Polymeric Device; Investigative Ophthalmology & Visual Science, May, 1994, vol. 35, No. 6; pp. 2815-2819.|
|9||*||Krupin; Krupin Eye Valve; Hood Laboratories Catalogue F 079 Rev Nov. 1992, four pages unnumbered.|
|10||*||Michelson et al; Experimental Treated With An Implantable Osmotic Minipump; Arch Ophthalmol, vol. 97, Jul. 1979; pp. 1345 1346.|
|11||Michelson et al; Experimental Treated With An Implantable Osmotic Minipump; Arch Ophthalmol, vol. 97, Jul. 1979; pp. 1345-1346.|
|12||*||Miki, et al; A Method For Chronic Drug Infusion Into the Eye; Japanese Journal of Ophthalmology, vol. 28:140 146, 1984.|
|13||Miki, et al; A Method For Chronic Drug Infusion Into the Eye; Japanese Journal of Ophthalmology, vol. 28:140-146, 1984.|
|14||*||Optimed; The optimed Advantage Glaucoma Pressure Regulator; Optimed Advertising Brochure, seven pages unnumbered; Jour. Glaucoma, vol. 2/3, 1993.|
|15||*||Rubsamen et al; Prevention of Experimental Proliferative Vitreoretinopathy With a Biodegradable Intravitreal Implant for the Sustained Release of Fluorouracil; Arch Ophthalmol, vol. 112, Mar.1994; pp. 407 413.|
|16||Rubsamen et al; Prevention of Experimental Proliferative Vitreoretinopathy With a Biodegradable Intravitreal Implant for the Sustained Release of Fluorouracil; Arch Ophthalmol, vol. 112, Mar.1994; pp. 407-413.|
|17||*||Sanborn et al; Sustained Release Ganciclovir Therapy for Treatment of Cytomegalovirus Retinitis; Arch Ophthmol, vol. 110, Feb. 1992; pp. 188 195.|
|18||Sanborn et al; Sustained-Release Ganciclovir Therapy for Treatment of Cytomegalovirus Retinitis; Arch Ophthmol, vol. 110, Feb. 1992; pp. 188-195.|
|Brevet citant||Date de dépôt||Date de publication||Déposant||Titre|
|US6024719 *||6 juil. 1998||15 févr. 2000||Morris; Robert E||Method and apparatus for performing surgery inside the human retina using fluidic internal limiting membrane (ILM) seperation (FILMS)|
|US6210357||15 juil. 1999||3 avr. 2001||Robert E Morris||Apparatus for performing surgery inside the human retina using fluidic internal limiting membrane (ILM) separation (films)|
|US6251090 *||2 nov. 1998||26 juin 2001||Robert Logan Avery||Intravitreal medicine delivery|
|US6358536||2 oct. 1998||19 mars 2002||Thomas Jefferson University||Nitric oxide donor compositions, methods, apparatus, and kits for preventing or alleviating vasoconstriction or vasospasm in a mammal|
|US6413245||4 oct. 2000||2 juil. 2002||Alcon Universal Ltd.||Sub-tenon drug delivery|
|US6413540||12 sept. 2000||2 juil. 2002||Alcon Universal Ltd.||Drug delivery device|
|US6416777||19 sept. 2000||9 juil. 2002||Alcon Universal Ltd.||Ophthalmic drug delivery device|
|US6471666||24 févr. 2000||29 oct. 2002||Steven A. Odrich||Injectable glaucoma device|
|US6589203 *||1 août 2000||8 juil. 2003||Peter Mitrev||Glaucoma drainage device implant|
|US6669950||1 juil. 2002||30 déc. 2003||Alcon, Inc.||Ophthalmic drug delivery device|
|US6808719||1 juil. 2002||26 oct. 2004||Alcon, Inc.||Drug delivery device|
|US6969525||8 juin 2002||29 nov. 2005||James C. Y. Chow||Surgically implanted time release medication for post-surgical treatment of a patient|
|US6986900||5 nov. 2003||17 janv. 2006||Alcon, Inc.||Ophthalmic drug delivery device|
|US7094226||12 nov. 2003||22 août 2006||Alcon, Inc.||Ophthalmic drug delivery device|
|US7108685 *||15 avr. 2002||19 sept. 2006||Boston Scientific Scimed, Inc.||Patch stabilization of rods for treatment of cardiac muscle|
|US7195774||28 août 2002||27 mars 2007||Carvalho Ricardo Azevedo Ponte||Implantable and sealable system for unidirectional delivery of therapeutic agents to tissues|
|US7195776||11 sept. 2006||27 mars 2007||Boston Scientific Scimed, Inc.||Patch stabilization of rods for treatment of cardiac muscle|
|US7220225 *||20 avr. 2006||22 mai 2007||Retinalabs, Inc.||Intraocular radiotherapy treatment|
|US7223225||18 nov. 2005||29 mai 2007||Retinalabs, Inc.||Intraocular radiotherapy treatment for macular degeneration|
|US7276019||8 mars 2005||2 oct. 2007||Retinalabs, Inc.||Ophthalmic treatment apparatus|
|US7563222||21 juil. 2009||Neovista, Inc.||Methods and apparatus for intraocular brachytherapy|
|US7563255||2 mai 2002||21 juil. 2009||Massachusetts Eye And Ear Infirmary||Implantable drug delivery device and use thereof|
|US7585517||20 sept. 2004||8 sept. 2009||Macusight, Inc.||Transscleral delivery|
|US7641627 *||5 janv. 2010||Camras Carl B||Method and apparatus for reducing intraocular pressure|
|US7678827||16 mars 2010||Alcon, Inc.||Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use|
|US7744520||29 juin 2010||Neovista, Inc.||Method and apparatus for intraocular brachytherapy|
|US7749528||6 juil. 2010||Ricardo Azevedo Pontes De Carvalho||Implantable and sealable medical device for unidirectional delivery of therapeutic agents to tissues|
|US7794437||26 janv. 2004||14 sept. 2010||Doheny Retina Institute||Reservoirs with subretinal cannula for subretinal drug delivery|
|US7803102||28 sept. 2010||Neovista, Inc.||Methods and apparatus for intraocular brachytherapy|
|US7803103||28 sept. 2010||Neovista Inc.||Methods and apparatus for intraocular brachytherapy|
|US7824704||2 nov. 2010||Surmodics, Inc.||Controlled release bioactive agent delivery device|
|US7887508||14 mars 2007||15 févr. 2011||The University Of Southern California||MEMS device and method for delivery of therapeutic agents|
|US7943162||17 mai 2011||Alcon, Inc.||Drug delivery device|
|US7951060||31 mai 2011||Neovista, Inc.||Methods and apparatus for intraocular brachytherapy|
|US7976520 *||12 juil. 2011||Nulens Ltd.||Eye wall anchored fixtures|
|US7976862||12 juil. 2011||Surmodics, Inc.||Controlled release bioactive agent delivery device|
|US8021680||29 avr. 2004||20 sept. 2011||Surmodics, Inc.||Controlled release bioactive agent delivery device|
|US8034369||12 sept. 2005||11 oct. 2011||Surmodics, Inc.||Controlled release bioactive agent delivery device|
|US8096972||17 janv. 2012||Johns Hopkins University||Devices for intraocular drug delivery|
|US8100818||24 janv. 2012||TDH Partners, Inc.||Beta radiotherapy emitting surgical device and methods of use thereof|
|US8177747||30 nov. 2010||15 mai 2012||Alcon Research, Ltd.||Method and apparatus for drug delivery|
|US8178576||3 juin 2008||15 mai 2012||Novartis Ag||Non-polymeric lipophilic pharmaceutical implant compositions for intraocular use|
|US8222271||23 mars 2007||17 juil. 2012||Santen Pharmaceutical Co., Ltd.||Formulations and methods for vascular permeability-related diseases or conditions|
|US8231608||31 juil. 2012||Minipumps, Llc||Drug-delivery pumps and methods of manufacture|
|US8231609||31 juil. 2012||Minipumps, Llc||Drug-delivery pumps and methods of manufacture|
|US8246569 *||16 août 2005||21 août 2012||California Institute Of Technology||Implantable intraocular pressure drain|
|US8246974||21 août 2012||Surmodics, Inc.||Medical devices and methods for producing the same|
|US8277830||4 oct. 2011||2 oct. 2012||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8292795||23 oct. 2012||Neovista, Inc.||Methods and apparatus for intraocular brachytherapy|
|US8298578||30 oct. 2012||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8308686||28 mai 2010||13 nov. 2012||The University Of Southern California||MEMS device and method for delivery of therapeutic agents|
|US8348897||8 janv. 2013||Minipumps, Llc||Implantable drug-delivery devices, and apparatus and methods for filling the devices|
|US8353812||3 juin 2009||15 janv. 2013||Neovista, Inc.||Handheld radiation delivery system|
|US8365721||27 août 2010||5 févr. 2013||Neovista Inc.||Methods and apparatus for intraocular brachytherapy|
|US8367097||12 mai 2010||5 févr. 2013||Santen Pharmaceutical Co., Ltd.||Liquid formulations for treatment of diseases or conditions|
|US8372036||12 févr. 2013||Alcon Research, Ltd.||Multi-layer heat assembly for a drug delivery device|
|US8399006||19 mars 2013||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8469934||25 janv. 2011||25 juin 2013||Alcon Research, Ltd.||Pulsatile peri-corneal drug delivery device|
|US8480638 *||4 oct. 2007||9 juil. 2013||Aciont, Inc.||Intraocular iontophoretic device and associated methods|
|US8486052||27 déc. 2010||16 juil. 2013||The Johns Hopkins University School Of Medicine||Reservoir device for intraocular drug delivery|
|US8486278||8 mai 2009||16 juil. 2013||Minipumps, Llc||Drug-delivery pumps and methods of manufacture|
|US8486960||21 juin 2012||16 juil. 2013||Santen Pharmaceutical Co., Ltd.||Formulations and methods for vascular permeability-related diseases or conditions|
|US8492400||9 févr. 2007||23 juil. 2013||Santen Pharmaceutical Co., Ltd.||Stable formulations, and methods of their preparation and use|
|US8529538||3 juil. 2012||10 sept. 2013||Minipumps, Llc||Drug-delivery pumps and methods of manufacture|
|US8585630||23 juil. 2012||19 nov. 2013||California Institute Of Technology||Implantable intraocular pressure drain|
|US8623395||5 août 2011||7 janv. 2014||Forsight Vision4, Inc.||Implantable therapeutic device|
|US8632511||5 mai 2010||21 janv. 2014||Alcon Research, Ltd.||Multiple thermal sensors in a multiple processor environment for temperature control in a drug delivery device|
|US8637070||9 févr. 2006||28 janv. 2014||Santen Pharmaceutical Co., Ltd.||Rapamycin formulations and methods of their use|
|US8658667||24 juin 2013||25 févr. 2014||Santen Pharmaceutical Co., Ltd.||Stable formulations, and methods of their preparation and use|
|US8663639||18 août 2008||4 mars 2014||Santen Pharmaceutical Co., Ltd.||Formulations for treating ocular diseases and conditions|
|US8764708||11 juin 2012||1 juil. 2014||The University Of Southern California||MEMS device and method for delivery of therapeutic agents|
|US8795712||7 mai 2013||5 août 2014||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8808727||15 mars 2013||19 août 2014||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US8905963||7 mai 2013||9 déc. 2014||Forsight Vision4, Inc.||Injector apparatus and method for drug delivery|
|US8927005||14 janv. 2013||6 janv. 2015||Santen Pharmaceutical Co., Ltd.||Liquid formulations for treatment of diseases or conditions|
|US9033911||5 août 2011||19 mai 2015||Forsight Vision4, Inc.||Injector apparatus and method for drug delivery|
|US9050407||10 déc. 2012||9 juin 2015||Minipumps, Llc||Implantable drug-delivery devices, and apparatus and methods for filling the devices|
|US9066779||3 janv. 2014||30 juin 2015||Forsight Vision4, Inc.||Implantable therapeutic device|
|US9107995||7 juin 2013||18 août 2015||Minipumps, Llc||Drug-delivery pumps and methods of manufacture|
|US9162024||8 mai 2009||20 oct. 2015||Minipumps, Llc||Drug-delivery pumps and methods of manufacture|
|US9180046||15 juil. 2013||10 nov. 2015||The Johns Hopkins University School Of Medicine||Reservoir device for intraocular drug delivery|
|US9180050||19 juin 2013||10 nov. 2015||California Institute Of Technology||Implantable intraocular pressure drain|
|US9186274 *||25 août 2009||17 nov. 2015||Camras Vision Inc.||Method and apparatus for reducing intraocular pressure|
|US9199035||18 août 2010||1 déc. 2015||Minipumps, Llc.||Drug-delivery pumps with dynamic, adaptive control|
|US9271866||28 juin 2013||1 mars 2016||University Of Southern California||Apparatus and methods for delivering therapeutic agents|
|US9283322||11 juil. 2013||15 mars 2016||Minipumps, Llc||Drug-delivery pump with dynamic, adaptive control|
|US9308124||19 déc. 2008||12 avr. 2016||University Of Southern California||Apparatus and methods for delivering therapeutic agents|
|US9308355||31 mai 2013||12 avr. 2016||Surmodies, Inc.||Apparatus and methods for coating medical devices|
|US9333297||24 sept. 2013||10 mai 2016||Minipumps, Llc||Drug-delivery pump with intelligent control|
|US9381153||25 nov. 2014||5 juil. 2016||Santen Pharmaceutical Co., Ltd.||Liquid formulations for treatment of diseases or conditions|
|US9387165||9 janv. 2014||12 juil. 2016||Santen Pharmaceutical Co., Ltd.||Rapamycin formulations and methods of their use|
|US9417238||14 nov. 2013||16 août 2016||Forsight Vision4, Inc.||Posterior segment drug delivery|
|US9452156||30 avr. 2013||27 sept. 2016||Santen Pharmaceutical Co., Ltd.||Formulations and methods for vascular permeability-related diseases or conditions|
|US20030064088 *||28 août 2002||3 avr. 2003||Carvalho Ricardo Azevedo Pontes De||Implantable and sealable system for unidirectional delivery of therapeutic agents to tissues|
|US20030195527 *||15 avr. 2002||16 oct. 2003||Helmus Michael N.||Patch stabilization of rods for treatment of cardiac muscle|
|US20030228356 *||8 juin 2002||11 déc. 2003||Chow James C.Y.||Surgically implanted time release medication for post-surgical treatment of a patient|
|US20040081633 *||28 oct. 2002||29 avr. 2004||Mercier Michel F.||Transparent oil-in-water emulsion|
|US20040092911 *||5 nov. 2003||13 mai 2004||Yoseph Yaacobi||Ophthalmic drug delivery device|
|US20040131654 *||30 oct. 2003||8 juil. 2004||Yoseph Yaacobi||Ophthalmic drug delivery device|
|US20040131655 *||30 oct. 2003||8 juil. 2004||Yoseph Yaacobi||Ophthalmic drug delivery device|
|US20040133155 *||19 déc. 2003||8 juil. 2004||Varner Sign Erickson||Devices for intraocular drug delivery|
|US20050019371 *||29 avr. 2004||27 janv. 2005||Anderson Aron B.||Controlled release bioactive agent delivery device|
|US20050112175 *||4 oct. 2004||26 mai 2005||Yoseph Yaacobi||Drug delivery device|
|US20050113806 *||15 mars 2004||26 mai 2005||De Carvalho Ricardo A.P.||Implantable and sealable medical device for unidirectional delivery of therapeutic agents to tissues|
|US20060039952 *||12 oct. 2005||23 févr. 2006||Yoseph Yaacobi||Ophthalmic drug delivery device|
|US20060069340 *||3 nov. 2005||30 mars 2006||Solx, Inc.||Shunt for the treatment of glaucoma|
|US20060189838 *||20 avr. 2006||24 août 2006||Dejuan Eugene Jr||Intraocular radiotherapy treatment|
|US20060189915 *||23 févr. 2005||24 août 2006||Camras Carl B||Method and apparatus for reducing intraocular pressure|
|US20060253151 *||11 juil. 2006||9 nov. 2006||Nun Joshua B||Eye wall anchored fixtures|
|US20060258994 *||1 mai 2006||16 nov. 2006||Avery Robert L||Implantable delivery device for administering pharmacological agents to an internal portion of a body|
|US20070005016 *||20 juin 2005||4 janv. 2007||Williams David F||Ocular injection device and method|
|US20070010799 *||11 sept. 2006||11 janv. 2007||Helmus Michael N||Patch stabilization of rods for treatment of cardiac muscle|
|US20070092570 *||7 déc. 2006||26 avr. 2007||Missel Paul J||Drug delivery device|
|US20070184089 *||3 avr. 2007||9 août 2007||Alcon, Inc.||Non-Polymeric Lipophilic Pharmaceutical Implant Compositions for Intraocular Use|
|US20080039792 *||14 mars 2007||14 févr. 2008||Ellis Meng||Mems device and method for delivery of therapeutic agents|
|US20080161741 *||18 mars 2008||3 juil. 2008||Becton, Dickinson And Company||Ocular implant and methods for making and using same|
|US20080241224 *||3 juin 2008||2 oct. 2008||Alcon, Inc.||Non-Polymeric Lipophilic Pharmaceutical Implant Compositions For Intraocular Use|
|US20080261219 *||4 avr. 2006||23 oct. 2008||Dxs Limited||Polynucleotide Primers|
|US20090093780 *||4 oct. 2007||9 avr. 2009||Tuitupou Anthony L||Intraocular iontophoretic device and associated methods|
|US20090192493 *||2 janv. 2009||30 juil. 2009||University Of Southern California||Implantable drug-delivery devices, and apparatus and methods for refilling the devices|
|US20090240215 *||19 déc. 2008||24 sept. 2009||Mark Humayun||Apparatus and methods for delivering therapeutic agents|
|US20090306585 *||8 mai 2009||10 déc. 2009||Changlin Pang||Implantable pumps and cannulas therefor|
|US20090306594 *||8 mai 2009||10 déc. 2009||Changlin Pang||Drug-delivery pumps and methods of manufacture|
|US20090306595 *||8 mai 2009||10 déc. 2009||Jason Shih||Implantable drug-delivery devices, and apparatus and methods for filling the devices|
|US20090311133 *||17 déc. 2009||Changlin Pang||Drug-delivery pumps and methods of manufacture|
|US20100004639 *||7 janv. 2010||Changlin Pang||Drug-delivery pumps and methods of manufacture|
|US20100057055 *||4 mars 2010||Camras Carl B||Method and apparatus for reducing intraocular pressure|
|US20100189765 *||25 nov. 2009||29 juil. 2010||Erickson Signe R||Implantable ocular drug delivery device and methods|
|US20100305550 *||28 mai 2010||2 déc. 2010||Ellis Meng||Mems device and method for delivery of therapeutic agents|
|US20110077582 *||13 oct. 2010||31 mars 2011||Tuitupou Anthony L||Intraocular iontophoretic device and associated methods|
|US20110125090 *||26 mai 2011||Peyman Gholam A||Ophthalmic drug delivery system and method|
|US20110144617 *||16 juin 2011||The University Of Southern California||Mems device and method for delivery of therapeutic agents|
|US20110144619 *||16 juin 2011||The University Of Southern California||Mems device and method for delivery of therapeutic agents|
|US20110184358 *||28 juil. 2011||Weiner Alan L||Pulsatile peri-corneal drug delivery device|
|US20110202032 *||18 août 2010||18 août 2011||Jason Shih||Drug-delivery pumps with dynamic, adaptive control|
|US20140276329 *||15 mars 2013||18 sept. 2014||Abbott Medical Optics Inc.||Trans-sclera portal for delivery of therapeutic agents|
|EP2329821A1||29 nov. 2006||8 juin 2011||GlaxoSmithKline LLC||Treatment of ocular neovascular disorders such as macular degeneration, angiod streaks, uveitis and macular edema|
|EP2374451A2||27 juil. 2006||12 oct. 2011||University of Florida Research Foundation, Inc.||Histone deacetylase inhibitors (HDAC) that correct protein misfolding and uses thereof|
|EP2944628A1||27 nov. 2012||18 nov. 2015||Bikam Pharmaceuticals, Inc.||Opsin-binding ligands, compositions and methods of use|
|WO1999018949A1 *||2 oct. 1998||22 avr. 1999||Thomas Jefferson University||Nitric oxide donor compositions, methods, apparatus, and kits for preventing or alleviating vasoconstriction or vasospasm in a mammal|
|WO2004066871A2 *||26 janv. 2004||12 août 2004||Doheny Retina Institute||Reservoirs with subretinal cannula for subretinal drug delivery|
|WO2004066871A3 *||26 janv. 2004||25 nov. 2004||Doheny Retina Inst||Reservoirs with subretinal cannula for subretinal drug delivery|
|WO2006052669A2 *||3 nov. 2005||18 mai 2006||Solx, Inc.||Shunt for the treatment of glaucoma|
|WO2011039648A1||29 sept. 2010||7 avr. 2011||Glaxo Wellcome Manufacturing Pte Ltd.||Methods of administration and treatment|
|WO2011094170A1||25 janv. 2011||4 août 2011||Alcon Research, Ltd.||Pulsatile peri-corneal drug delivery device|
|WO2011101833A2 *||22 févr. 2011||25 août 2011||Microsert Ltd.||Slow release liquid drug delivery device|
|WO2011101833A3 *||22 févr. 2011||24 nov. 2011||Microsert Ltd.||Slow release liquid drug delivery device|
|WO2013058809A1||19 oct. 2012||25 avr. 2013||Bikam Pharmaceuticals, Inc.||Opsin-binding ligands, compositions and methods of use|
|Classification aux États-Unis||604/9, 604/294|
|Classification coopérative||A61F9/0017, A61M2210/0612|
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